Decoding the blueprint of receptor binding by filoviruses through large-scale binding assays and machine learning.

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作者:Lasso Gorka, Grodus Michael, Valencia Estefania, DeJesus Veronica, Liang Eliza, Delwel Isabel, Bortz Rob H 3rd, Lupyan Dmitry, Ehrlich Hanna Y, Castellanos Adrian A, Gazzo Andrea, Wells Heather L, Wacharapluesadee Supaporn, Tremeau-Bravard Alexandre, Seetahal Janine F R, Hughes Tom, Lee Jimmy, Lee Mei-Ho, Sjodin Anna R, Geldenhuys Marike, Mortlock Marinda, Navarrete-Macias Isamara, Gilardi Kirsten, Willig Michael R, Nava Alessandra F D, Loh Elisabeth H, Asrat Makda, Smiley-Evans Tierra, Magesa Walter S, Zikankuba Sijali, Wolking David, Suzán Gerardo, Ojeda-Flores Rafael, Carrington Christine V F, Islam Ariful, Epstein Jonathan H, Markotter Wanda, Johnson Christine K, Goldstein Tracey, Han Barbara A, Mazet Jonna A K, Jangra Rohit K, Chandran Kartik, Anthony Simon J
Evidence suggests that bats are important hosts of filoviruses, yet the specific species involved remain largely unidentified. Niemann-Pick C1 (NPC1) is an essential entry receptor, with amino acid variations influencing viral susceptibility and species-specific tropism. Herein, we conducted combinatorial binding studies with seven filovirus glycoproteins (GPs) and NPC1 orthologs from 81 bat species. We found that GP-NPC1 binding correlated poorly with phylogeny. By integrating binding assays with machine learning, we identified genetic factors influencing virus-receptor-binding and predicted GP-NPC1-binding avidity for additional filoviruses and bats. Moreover, combining receptor-binding avidities with bat geographic distribution and the locations of previous Ebola outbreaks allowed us to rank bats by their potential as Ebola virus hosts. This study represents a comprehensive investigation of filovirus-receptor binding in bats (1,484 GP-NPC1 pairs, 11 filoviruses, and 135 bats) and describes a multidisciplinary approach to predict susceptible species and guide filovirus host surveillance.

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